The present invention relates to novel cyclic amide compounds and medicines useful in preventing and treating allergic immunological diseases or the like, comprising such a compound as an active ingredient.
IgE, which is a kind of immunoglobulin (Ig), is an allergen-specific molecule produced by an IgE producing cell differentiated from a B cell. This process is triggered by the contact of an immunocyte with an allergen in vivo.
IgE is produced in a target organ for an allergy and binds to a receptor on the surface of a mast cell, which is a central effector cell in an allergic reaction, or a basophil (sensitized state). After the sensitization, allergic chemical mediators such as histamine, leukotrienes, prostaglandins and PAF, and injuring enzymes such as tryptase are released from the mast cell stimulated by the reaction of the specific IgE and an allergen which invades in the living body, so that immediate responses such as vascular permeability acceleration, smooth muscle constriction and vasodilation are elicited. Further, cytokines such as IL-4, which directly activate other immune system cells, are also secreted from the stimulated mast cell. As a result, eosinophils, basophils and the like infiltrate into a tissue, and the allergic chemical mediators and tissue injuring proteins such as MBP, which are secreted by these inflammatory cells, induce a late response, so that the allergic symptom is lingered and taken seriously ill.
From this, IgE is considered a substance fundamentally participating in the attack of an allergic immunological disease.
Therefore, several compounds having an inhibitory effect on the production of an IgE antibody have heretofore been found and reported with a view toward developing antiallergic agents [Pharmacology and Therapy, 1994, 22(3), 1369; Japanese Patent Application Laid-Open No. 106818/1989; Japanese Patent Publication No. 17506/1995; Japanese Patent Application Laid-Open Nos. 92216/1996 and 109177/1996; and WO 96/11682]. However, the object has been not always sufficiently achieved under the circumstances.
Accordingly, it is an object of the present invention to find a compound having a strong inhibitory effect on the production of an IgE antibody so as to provide a medicine effective for allergic immunological diseases, comprising this compound as an active ingredient.
With the foregoing circumstances in view, the present inventors have carried out an extensive investigation. As a result, it has been found that novel cyclic amide compounds represented by the general formula (1), which will be described subsequently, salts thereof, or solvates thereof have an excellent inhibitory effect on the production of an IgE antibody and are useful as medicines such as antiallergic agents, thus leading to completion of the present invention.
According to the present invention, there is thus provided a compound represented by the following general formula (1): 
wherein A is a residue of an alicyclic compound which may be substituted, an aromatic compound which may be substituted, or a heterocyclic compound which may be substituted;
X is a single bond; a lower alkylene group which may be substituted; a divalent residue of an alicyclic compound which may be substituted, an aromatic compound which may be substituted, or a heterocyclic compound which may be substituted; an imino group which may be substituted; or a sulfur atom or an oxygen atom;
Y is a single bond, or a lower alkylene, imino or lower alkylimino group;
Z is a group of xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94(CHxe2x95x90CH)2xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94Cxe2x89xa1Cxe2x80x94, or a divalent residue of benzene, pyridine, pyrimidine or pyrazine which may be substituted;
B is a nitrogen atom or xe2x95x90CHxe2x80x94; and
m and n are the same or different from each other and independently an integer of 1 to 4,
a salt thereof, or a solvate thereof.
According to the present invention, there is also provided a medicine comprising the above compound (1) as an active ingredient.
According to the present invention, there is further provided a medicinal composition comprising the above compound (1) and a pharmaceutically acceptable carrier.
According to the present invention, there is still further provided use of the above compound (1) for a medicine.
According to the present invention, there is yet still further provided a method of treating an allergic immunological disease, which comprises administering the above compound (1).
In the present invention, examples of the alicyclic compound represented by A or X include saturated or unsaturated alicyclic compounds having 3 to 14 carbon atoms, for example, cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane; cycloalkenes such as cyclopentene and cyclohexene; and bicyclic fused cycloalkenes such as indene, indane, dihydronaphthalene and tetrahydronaphthalene.
Examples of the aromatic compound include aromatic compounds having 5 to 14 carbon atoms, such as benzene and naphthalene.
Examples of the heterocyclic compound include 5- to 7-membered heterocyclic compounds containing 1 to 3 nitrogen atoms, such as pyrrolidine, pyridine, piperidine, piperazine and homopiperazine.
Examples of the lower alkylene group represented by X or Y include linear or branched alkylene groups having 1 to 8 carbon atoms, and specifically, methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and octamethylene groups.
In the formula (1), it is particularly preferred that A be a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group. These groups may have 1 to 3 substituents. Here, examples of the substituents on these groups include a hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1 to 3 halogen atoms, lower alkoxy groups, an amino group, monoalkylamino groups, dialkylamino groups, and lower alkylthio groups. As A, a phenyl group substituted by 1 to 3 substituents selected from among lower alkyl groups and lower alkoxy groups is particularly preferred.
The lower alkylene group represented by X is preferably a linear or branched alkylene group having 1 to 8 carbon atoms. A linear alkylene group having 2 to 4 carbon atoms is more preferred. These groups may have substituents such as halogen atoms, or hydroxyl, lower alkoxy, amino, monoalkylamino, dialkylamino, carboxyl or lower alkoxycarbonyl groups. Of these, a lower alkylene group which may be substituted by an amino, monoalkylamino, dialkylamino, carboxyl or lower alkoxycarbonyl group is particularly preferred.
The divalent residue of the alicyclic compound, which is represented by X, is preferably a divalent residue of a cycloalkane having 5 to 8 carbon atoms. Examples of the divalent residue of the aromatic compound, which is represented by X, include phenylene and naphthylene groups, with the phenylene group being particularly preferred. Here, the phenylene group may be any of 1,2-phenylene, 1,3-phenylene and 1,4-phenylene groups, with the 1,2-phenylene or 1,4-phenylene group being particularly preferred. Preferable examples of the divalent residue of the heterocyclic compound, which is represented by X, include divalent residues of pyridine, pyrrolidine, piperidine, piperazine and homopiperazine. The divalent residue of the alicyclic compound, aromatic compound or heterocyclic compound, or the imino group, which is represented by X, may be substituted by a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted by an amino, monoalkylamino or dialkylamino group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, an amino group, an alkylamino group, a dialkylamino group, a nitro group, a cyano group, an aralkyl group, or the like. Here, examples of the alkylamino and dialkylamino groups include lower alkylamino groups and di-lower alkylamino groups, respectively.
It is preferred that X be the alkylene group having 1 to 8 carbon atoms, the divalent residue of the aromatic compound which may be substituted, or the divalent residue of the heterocyclic compound which may be substituted.
Y is preferably a single bond or an alkylene group having 1 to 8 carbon atoms.
Examples of groups which may be substituted on the divalent residue of benzene, pyridine, pyrimidine or pyrazine represented by Z include halogen atoms, and lower alkyl, lower alkoxy, amino and nitro groups. Z is preferably a divalent residue of benzene which may be substituted.
The group 
is particularly preferably a 1,4-piperazinyl, 1,4-homopiperazinyl or 1,4-piperidinyl group.
In the above-described various substituent groups or the like, xe2x80x9calkylxe2x80x9d in the alkyl groups, alkylamino groups, dialkylamino groups, alkylthio groups and the like generally includes linear or branched alkyl having 1 to 12 carbon atoms. Of these, lower alkyl groups are preferred. The lower alkyl groups include linear or branched alkyl groups having 1 to 8 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl groups. Of these, those having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl groups, are particularly preferred.
xe2x80x9cAlkoxyxe2x80x9d in the alkoxy groups, alkoxycarbonyl groups and the like generally includes linear or branched alkoxy having 1 to 12 carbon atoms. Of these, lower alkoxy groups are preferred. The lower alkoxy groups include linear or branched alkoxy groups having 1 to 8 carbon atoms. Specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy groups. Of these alkoxy groups, those having 1 to 6 carbon atoms are preferred.
Examples of the aralkyl group include C6-14-aryl-C1-8-alkyl groups such as benzyl, phenylethyl and naphthylmethyl groups.
Examples of the lower alkylthio group include alkylthio groups having 1 to 8 carbon atoms.
The halogen atoms include fluorine, chlorine, bromine and iodine atoms.
No particular limitation is imposed on the salts of the cyclic amide compounds (1) according to the present invention so far as they are pharmaceutically acceptable salts. In the case where the cyclic amide compounds (1) are basic compounds, however, examples of the salts include mineral acid salts such as hydrochlorides, sulfates and nitrates; and organic acid salts such as methanesulfonates, acetates, oxalates and citrates. In the case where the cyclic amide compounds (1) are acidic compounds on the other hand, examples of the salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and organic base salts such as pyridine salts, picoline salts and triethylamine salts.
The cyclic amide compounds (1) may be present in the form of solvates such as hydrates.
The cyclic amide compounds (1) according to the present invention can be prepared according to, for example, the following reaction formula: 
wherein A, X, Y, Z, B, m and n have the same meanings as defined above.
More specifically, the compounds (1) according to the present invention are obtained by the N-acylating reaction of a carboxylic acid (2) with a diamine (3).
The N-acylating reaction may be conducted by using any N-acylating reaction known per se in the art. It is preferable to apply, for example, (a) a method in which the carboxylic acid (2) and the diamine (3) are reacted in the presence of a condensation reagent, preferably, in the presence of a condensation reagent and a base, in a solvent, or (b) a method in which a reactive derivative of the carboxylic acid and the diamine (3) are reacted in a solvent, preferably, in the presence of a base.
Examples of the solvents used in these reactions may include dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, methylene chloride and dichloroethane. As the base, may be used an organic base such as pyridine, triethylamine or diisopropylethylamine, or an inorganic base such as sodium carbonate or sodium hydrogencarbonate. Examples of usable condensation reagents include 1,3-dicyclohexylcarbodiimide, 1-cyclohexyl-3-morpholinoethyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1,1xe2x80x2-carbonyldiimidazole, diethyl phosphorocyanidate, diphenylphosphoryl azide, bis(2-oxo-3-oxazolidinyl)-phosphinic chloride and 2-chloro-1-methylpyridinium iodide. Examples of usable derivatives of the carboxylic acid include acid halides such as acid chlorides, acid azides, symmetric acid anhydrides, mixed anhydrides with pivalic acid or the like, and active esters such as cyanomethyl esters and p-nitrophenyl esters.
In each of the method (a) and the method (b), the N-acylating reaction is completed by reacting the carboxylic acid (2) or the reactive derivative thereof with the diamine (3) at a reaction temperature of 0xc2x0 C. to 100xc2x0 C. for 30 minutes to 30 hours. The isolation and purification of the compound (1) from the reaction mixture may be conducted by using any methods known per se in the art, for example, filtration, extraction, washing, drying, concentration, recrystallization and various kinds of chromatography.
The compound (1) thus obtained may be converted into an acid-addition salt or a base salt in a method known per se in the art.
The compound (1) may also be converted into a solvate with a reaction solvent, solvent for recrystallization, or the like, in particular, a hydrate.
Since the cyclic amide compounds (1) according to the present invention have an excellent inhibitory effect on the production of an IgE antibody as demonstrated in Test Example, which will be described subsequently, and inhibitory effects on the production of IL-4 and IL-5, they are useful as medicines for prevention and treatment of various allergic immunological diseases, for example, asthma, atopic dermatitis, allergic rhinitis, inflammatory bowel disease, contact dermatitis, allergic ophthalmopathy and the like.
The cyclic amide compounds (1) or the salts thereof according to the present invention can be formulated into medicinal composition, for example, various oral and parenteral preparations in the form of a solid, semisolid or liquid by adding a pharmaceutically acceptable, inorganic or organic carrier in accordance with a method known per se in the art.
Examples of the oral preparations include tablets, pills, granules, soft and hard capsules, powders, grains, triturations, emulsions, syrups, pellets and elixirs. Examples of the parenteral preparations include injections, drops, infusions, ointments, lotions, tonics, sprays, suspensions, oils, emulsions, suppositories and eye drops.
The active ingredients according to the present invention may be formulated into various preparations in accordance with a method known per se in the art. In these preparations, may be suitably used surfactants, excipients, colorants, smell corrigents, preservatives, stabilizers, buffers, suspension stabilizers, isotonic agents and the like, as needed.
The dose of the cyclic amide compound (1) or the salt thereof varies according to the kind of the compound, the kind of a disease to be treated or prevented, an administration method, the age, sex and weight of a patient to be administered, treatment time, and the like. However, the compound may be administered in a dose of 0.01 to 1,000 mg/kg of weight/day. The compound may be administered at once or in several portions, for example, 2 to 6 portions a day.